The major focus of the Geriatric Psychiatry Branch (GPB) is the study of individuals with memory disorders as a result of age or neurodegeneration and those at risk for these disorders. The efforts of the Neuroimaging Section are focused on identifying markers that can be usefully employed to determine whether an individual is on a trajectory leading to minimal cognitive impairment (MCI) and/or Alzheimer?s disease (AD) or are on a successful aging trajectory. Should we fall short of the above goal, it is still likely that these studies will contribute to one or more of the following objectives: improving AD diagnosis and evaluation, our understanding of the pathophysiology of the disorder, the ability to observe central nervous system adaptation and plasticity, and/or an uncovering of new therapeutic targets for MCI and AD. Our studies use both cross-sectional and longitudinal approaches. In particular, they frequently take advantage of the fact that individuals with a form of the apolipoprotein E gene called the APOE-epsilon-4 allele are at increased risk of developing AD and of developing AD at an earlier age. The work may be conveniently divided into structural, functional and chemical approaches. Chemical: Memory is the most important earliest clinical symptom of Alzheimer?s disease (AD). There is evidence that the cholinergic system has an important role in normal memory, at least in part through its influence on hippocampal function, in age-related memory loss, and in AD. Medications designed to enhance the cholinergic system through increasing concentrations of the neurotransmitter acetylcholine in the synapse are the only approved drugs for the treatment of AD. The Neuroimaging Section of GPB has been using positron emission tomography (PET) to study the cholinergic system. Because, the precise effects of normal aging on the cholinergic system are unknown as both in vitro and PET studies have shown conflicting results, our first specific objectives were to determine whether we could accurately and reliably measure attributes of the cholinergic system in regions of the brain of awake humans with PET, and whether we could establish if there were any changes in these attributes as individuals age. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (18F P-TZTP) suggested the use of 18FP-TZTP to selectively quantify M2 receptors in humans. In this study, we used 18FP-TZTP, to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 ? 5.5 y) and 20 healthy older subjects (mean age = 62.1? 7.7 y). Corrections for subject motion during the 120 min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (VT) of 18FP-TZTP. Within both groups of subjects, volumes of distribution (K1/k2) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of 18FP-TZTP throughout much of the cerebellum, cortex and subcortex (Global Gray VT = 742 ? 163 in older subjects and 645 ? 74 in younger subjects, p < 0.03). Across all subjects 18FP-TZTP, regional and Global Gray distribution volumes were significantly correlated to age (Global Gray VT, r = 0.41, p < .01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation of the data. The increased variance in the 18FP-TZTP distribution volumes of older subjects suggested the possibility that there might be a subset of the older subjects that had the higher distribution volumes. The apolipoprotein E-e4 allele (APOE-e4) confers an increased susceptibility to age-related memory problems and Alzheimer?s disease. To determine the effect of the APOE-e4 allele on the muscarinic component of the cholinergic system of aging subjects, the distribution volumes (VT) of [18F]FP-TZTP of 10 healthy subjects with APOE-e4 alleles (APOE-e4+) and 10 without (APOE-e4-), ranging in age from 52 to 75 years, were compared. Regional cerebral blood flow (rCBF) measurements with H215O were also determined in the same subjects and compared. Global Gray VT (840 ? 155 ml plasma/ml tissue) was greater in APOE-e4+ subjects than APOE-e4- subjects (660 ? 113 ml plasma/ml tissue, p = 0.01), and previously studied younger subjects. There were no significant differences between the groups with respect to rCBF, but within the APOE-e4+ group there was a trend for subjects with the higher Global Gray VTs to have lower Global Gray CBFs (r = -.65, p < .06). Thus, our working hypothesis is that the higher [18F]FP-TZTP distribution volumes result from a direct adverse interaction between the APOE-e4 allele and the aging process on the muscarinic system, and may relate directly to the release of acetylcholine into the synapse. In an effort to indirectly measure these levels, we have begun studies using physostigmine a drug that inhibits acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine once it is in the synapse. Preclinical monkey studies have demonstrated that physostigmine can increase acetylcholine levels in the synapse and result in a change in the distribution volume of [18F]FP-TZTP. Similar studies are now underway to establish whether a similar effect can be observed in humans with lower and more acceptable doses of physostigmine than those used in monkeys. Assuming that acetylcholine levels differ among APOE-epsilon4+ and APOE-epsilon4- subjects we expect to see a different tracer response to physostigmine in these two cohorts. Structural: In previous years we established intra and inter-rater reliabilities for the measurement of hippocampal volumes using sMRIs and a manual tracing method. Using these methods an increased rate of volume loss in the hippocampi of healthy older females with at least one APOE-e4 allele, an allele that infers increased susceptibility to the development of AD, was observed during a 2-year period. We have now completed the initial stages of a 6-year of longitudinal study designed to determine whether the rate of hippocampal volume loss during this period is linear in individuals who remain healthy and whether information pertaining to this rate is predictive of subsequent memory performance. The analysis of the first 25 subjects in now complete and a manuscript in preparation will describe that the rate is linear and those individuals with greater initial rates of volume loss perform more poorly on memory tests performed 6 years later. We have also established a new method of measuring ventricular volume over time. Our initial analysis of this data suggests a linear increase over time on this measure in healthy older subjects in their 7th and 8th decades. However, the changes in ventricular volume are not correlated with the changes in the hippocampus suggesting regionally specific processes in the medial temporal area. Functional: We have been measuring the regional brain activations of healthy older and younger subjects during the performance of a ?feature-binding? task using an fMRI BOLD approach and more directly using magnetoencephalography (MEG). The MEG results in young subjects were consistent with sources of activation in the thalamus, fusiform gyrus, parietal lobe, and dorsolateral prefrontal cortex. These regions are consistent with our own fMRI studies and those in the literature. However, additional areas of activation detectable by MEG included the parahippocampal gyrus, cingulate gyrus and caudate nucleus.